Category: 5738-14-7

King, F. E. published the artcileNew potential chemotherapeutic agents. VI. Derivatives of 2,4-diazaacridine, Application of 2-(Dimethylamino)pyrimidine-4,6-diol, the publication is Journal of the Chemical Society (1947), 726-34, database is CAplus and MEDLINE.

cf. C.A. 41, 3107d. Because of the interest in chemotherapy in compounds having a structural resemblance to riboflavin, attention has been turned to 2′,3′,4,5-quinolinopyrimidine, which has been designated 2,4-diazaacridine (cf. Conrad and Reinbach, Ber. 34, 1341(1901)), and especially to derivatives containing basic side chains. Mercaptobarbituric acid (I) (5 g.), 4.5 g. Et₂N(CH₂)₃NH₂, and about 2 mols. freshly prepared Pb(OH)₂ in iso-AmOH, refluxed 15 hrs., give 78% 2-(3-diethylaminopropylamino)-4,6-dihydroxypyrimidine (II), analyzed as the picrolonate, with 1 mol. H₂O (0.5 mol. lost at 100°, 1 mol. at 150°), yellow, m. 235° (decomposition). I (14.4 g.) and 8.4 g. NaHCO₃ in 200 cc. H₂O, shaken 30 min. with 12.6 g. Me₂SO₄ at room temperature, give 72% 4,6-dihydroxy-2-methylmercaptopyrimidine (III); 10 g. crude III and 3.9 g. Et₂N(CH₂)₃NH₂, heated 30 min. at 180°, give 92% II. EtO₂CCH₂CH₂COCl (6 g.) and 5.2 g. Et₂N(CH₂)₃NH₂ in ether at 0° give 60% α-carbethoxy N-(3-diethylaminopropyl)acetamide, b_0.05 115°, did not react with CO(NH₂)₂ in the presence of EtONa in EtOH (6 hrs.). EtO₂CCH₂C(OEt):NH.HCl (6 g.) and 4.2 g. Et₂N(CH₂)₃NH₂ in 100 cc. EtOH 12 hrs. at room temperature give Et₂N(CH₂)₃NHC(:NH)CH₂CO₂Et, whose picrolonate, with 1 mol. H₂O, yellow, m. 125-30°; this could not be condensed with H₂NCO₂Et. The action of Et₂N(CH₂)₃NH₂ on EtO₂CCH₂CONHCONH₂ gives barbituric acid and not Et₂N(CH₂)₂NHCOCH₂CONHCONH₂, which might have been cyclized to a pyrimidine. 2,4,6-Trichloropyrimidine (IV) (3 g.), added to 11 g. PhCH₂OH and 1.15 g. Na in 100 cc. PhMe (after formation of the alcoholate) and the mixture refluxed 2 hrs., gives 63% of the 2,4,6-tris(benzyloxy) derivative, m. 62-4°; the action of Na in liquid NH₃ does not give a pure compound; hydrogenation in AcOH over Pd-charcoal gives 84% barbituric acid. IV (18 g.) in 100 cc. Me₂CO, cautiously treated with 13 g. Et₂N(CH₂)₃NH₂ with cooling, gives 72% 2,6-dichloro-4-(3-diethylaminopropylamino)pyrimidine (V); HCl salt m. 149°; picrate, bright yellow, m. 162°; picrolonate, yellow, m. 164°. V (3.1 g.) and 10 cc. concentrated HCl, heated on the steam bath 12 hrs., give 76% of the di-HCl salt, m. 253° (decomposition), of 6-chloro-4-(3-diethylaminopropylamino)-2-hydroxypyrimidine; picrate, yellow, m. 209° (decomposition). V (6.25 g.), added in 10 portions to PhCH₂ONa (from 13 g. PhCH₂OH and 1.4 g. Na) in 100 cc. PhMe and the mixture heated 2 hrs., gives 80% 4-(3-diethylaminopropylamino)-2,6-bis(benzyloxy)pyrimidine (VI), m. 68° (dipicrate, m. 156°); crude VI in AcOH, hydrogenated over Pd-charcoal at room temperature and atm. pressure (4 hrs.), gives 4-(3-diethylaminopropylamino)-2,6-dihydroxypyrimidine (VII), apparently with 3 mols. AcOH, very hygroscopic; picrolonate m. 186° (decomposition); 1 of the 2 mols. of H₂O is lost at 100° and the 2nd at 130°. VII and p-ClC₆H₄N₂Cl give 57% of the 5-(p-chlorophenylazo) derivative, with 2 mols. H₂O (1 lost at 100°), yellow, m. 151° (decomposition) (dipicrate, m. 205° (decomposition)); catalytic reduction over RaneyNi gives a product rapidly oxidized in the air. Although VII was devoid of antimalarial activity, the 5-Me analog was also prepared but it was also inactive. 2,4,6-Trichloro-5-methylpyrimidine (19.7 g.) in 100 cc. Me₂CO, cautiously treated with 13 g. Et₂N(CH₂)₃NH₂ in 100 cc. Me₂CO and cooled to 4°, gives 60% of the HCl salt (VIII), m. 193-5°, of 2,6-dichloro-4-(3-diethylaminopropylamino)-5-methylpyrimidine, whose picrate m. 163°. VIII and PhCH₂ONa give the 2,6-bis(benzyloxy) derivative (IX), an oil (tripicrate, m. 141-2°). Hydrogenation of IX in AcOH over Pd-charcoal at room temperature and atm. pressure gives 7.2 g. 4-(3-diethylaminopropylamino)-2,6-dihydroxy-5-methylpyrimidine, as the triacetate (with 1 mol. H₂O); dipicrate, yellow, m. 183-4° (decomposition); picrolonate, yellow, m. 223° (decomposition). 4,6-Dichloro-2-methylaminopyrimidine (X) (4.4 g.) and PhCH₂ONa (from 1.15 g. Na) in 150 cc. PhMe, heated 1 hr. at 100°, give 27.5% 4-chloro-2-methylamino-6-(benzyloxy)pyrimidine, m. 120°; if the reaction mixture is refluxed 4 hrs., there results 61% 2-methylamino-4,6-bis(benzyloxy)pyrimidine, m. 101°; reduction (8 hrs.) in AcOH over Pd-charcoal gives 66.6% 2-methylamino-4,6-dihydroxypyrimidine (XI), with 0.5 mol. EtOH and 2/3 mols. H₂O, m. above 310°. 2,6-Dichloro-4-methylaminopyrimidine (6 g.) and PhCH₂ONa in 75 cc. PhMe, refluxed 3 hrs., give 69% 4-methylamino-2,6-bis(benzyloxy)pyrimidine, m. 118°; reduction (2.5 hrs.) in AcOH gives 98.8% 4-methylamino-2,6-dihydroxypyrimidine (XIA), m. 302° (decomposition). IV (15 g.) and 27 cc. 33% Me₂NH in 75 cc. EtOH give 48% 2,6-dichloro-4-dimethylaminopyrimidine (XII), m. 113°; with PhCH₂ONa in PhMe (refluxed 1 hr.), there results 69.5% 4-dimethylamino-2,6-bis(benzyloxy)pyrimidine, m. 79°; catalytic reduction gives 77% 4-dimethylamino-2,6-dihydroxypyrimidine, m. 320° (decomposition). The alc. mother liquor from XII yields 35% 4,6-dichloro-2-dimethylaminopyrimidine (XIII), m. 102-3°. XIII (3.5 g.) and PhCH₂ONa (from 0.84 g. Na) in 50 cc. PhMe, heated 1 hr. at 100°, give 73% 4-chloro-2-dimethylamino-6-(benzyloxy)pyrimidine, m. 84°; when refluxed 3 hrs., there results 69.5% 2-dimethylamino-4,6-bis(benzyloxy)pyrimidine, whose picrate, yellow, m. 176°; catalytic reduction gives 73% 2-dimethylamino-4,6-dihydroxypyrimidine, yellow, m. 320° (decomposition). IV (5.75 g.) in 90 cc. Me₂CO and the NH:C(NH₂)₂ from 6 g. of the HCl salt in 10 cc. H₂O, on standing 15 min., give 53% 2,6-dichloro-4-guanidinopyrimidine, m. 325° (decomposition); the mother liquor apparently contains an addnl. 43%; PhCH₂ONa in PhMe, heated 2 hrs. at 100°, gives 61% 6-chloro-4-guanidino-2-(benzyloxy)pyrimidine, m. 170° (picrate, yellow, m. 250° (decomposition)); refluxed in PhMe 8 hrs., there results 78% 4-guanidino-2,6-bis(benzyloxy)pyrimidine, characterized as the picrate, m. 200°; reduction yields 38% 4-guanidino-2,6-dihydroxypyrimidine (XIV), m. 300°. Malonylguanidine, CH:C(OH).N:C(NH₂).N:C(OH), (2 g.) and 3 g. o-H₂NC₆H₄CHO in 100 cc. H₂O containing 5 cc. HCl, heated 1 hr. on the steam bath, give 69.5% 3-amino-1-hydroxy-2,4-diazaacridine, analyzed as the HCl salt (with 2 mols. H₂O), m. above 310°; the free base, m. above 310°, gives a pale yellow solution in NaOH with a strong greenish blue fluorescence. 4-Amino-2,6-dihydroxypyrimidine and o-H₂NC₆H₄CHO give 61% 1,3-dihydroxy-2,4-diazaacridine (XV) (cf. Conrad and Reinbach, loc. cit.), which crystallizes with 1 mol. AcOH. 2,4-Diamino-6-hydroxypyrimidine (3 g.) in 100 cc. H₂O and 10 cc. AcOH, treated with 3 g. o-H₂NC₆H₄CHO in 10 cc. EtOH and refluxed 30 min., gives 35% (XVI) with 0.5 mol. H₂O, bright yellow, m. above 330°; its solutions exhibit a vivid blue fluorescence; HCl salt, biscuit-colored, m. above 310°. XI and o-H₂NC₆H₄CHO give 63.5% 3-methylamino-1-hydroxy-2,4-diazaacridine, with 4/3 mols. H₂O, pale yellow, m. above 310°; its solutions have a marked green-blue fluorescence; XIA gives XV. XIV gives 81% of the 1-guanidino analog of XV, m. above 310°; di-HCl salt, with 1.5 mols. H₂O, m. above 310°; at 120° it forms the mono-HCl salt, with 1 mol. H₂O; picrate, yellow, with 1.5 mols. H₂O, m. 230° (decomposition). The 3-(3-diethylaminopropylamino) analog of XV, obtained as a reddish oil, analyzed as the meconate (50% yield), with 5 mols. H₂O (2.5 mols. lost at 100°), pale yellow, m. 180° (decomposition); the picrate, with 1 mol. EtOH, m. 222° (decomposition) and could not be further purified. Barbituric acid (3.9 g.) and 3.9 g. 2,4-(O₂N)₂C₆H₃CHO in 150 cc. boiling H₂O give 71.5 g. of the 2,4-dinitrobenzylidene derivative, orange, m. above 310°; 2,4-H₂N(O₂N)C₆H₃CHO in dilute EtOH gives 64.5% 6-nitro-1,3-dihydroxy-2,4-diazaacridine, with 1 mol. EtOH, cream, m. above 310°; it forms an orange Na salt; in AcOH, it shows a blue fluorescence; the NO₂ group could not be reduced. These compounds were only slightly active or inactive when tested in vitro against Staphylococcus aureus.

Journal of the Chemical Society published new progress about 5738-14-7. 5738-14-7 belongs to pyrimidines, auxiliary class Pyrimidine,Amine,Alcohol,Pyrimidine, name is 2-(Dimethylamino)pyrimidine-4,6-diol, and the molecular formula is C6H9N3O2, Application of 2-(Dimethylamino)pyrimidine-4,6-diol.

Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia